title: Long distance directional growth of dopaminergic axons along pathways of netrin-1 and GDNF.
abstract: Different experimental and clinical strategies have been used to promote survival of transplanted embryonic ventral mesencephalic (VM) neurons. However, few studies have focused on the long-distance growth of dopaminergic axons from VM transplants. The aim of this study is to identify some of the growth and guidance factors that support directed long-distance growth of dopaminergic axons from VM transplants. Lentivirus encoding either glial cell line-derived neurotrophic factor (GDNF) or netrin-1, or a combination of lenti-GDNF with either lenti-GDNF family receptor α1 (GFRα-1) or lenti-netrin-1 was injected to form a gradient along the corpus callosum. Two weeks later, a piece of embryonic day 14 VM tissue was transplanted into the corpus callosum adjacent to the low end of the gradient. Results showed that tyrosine hydroxylase (TH(+)) axons grew a very short distance from the VM transplants in control groups, with few axons reaching the midline. In GDNF or netrin-1 expressing groups, more TH(+) axons grew out of transplants and reached the midline. Pathways co-expressing GDNF with either GFRα-1 or netrin-1 showed significantly increased axonal outgrowth. Interestingly, only the GDNF/netrin-1 combination resulted in the majority of axons reaching the distal target (80%), whereas along the GDNF/GFRα-1 pathway only 20% of the axons leaving the transplant reached the distal target. This technique of long-distance axon guidance may prove to be a useful strategy in reconstructing damaged neuronal circuits, such as the nigrostriatal pathway in Parkinson's disease.
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.forename: K S
authors.initials: KS
authors.lastname: Ziemba
authors.forename: A M
authors.initials: AM
authors.lastname: Fletcher
authors.forename: B
authors.initials: B
authors.lastname: Ghosh
authors.forename: E
authors.initials: E
authors.lastname: Truit
authors.forename: D M
authors.initials: DM
authors.lastname: Yurek
authors.forename: G M
authors.initials: GM
authors.lastname: Smith
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D015153:Blotting, Western; D016380:Brain Tissue Transplantation / Q000379:methods*; D059290:Dopaminergic Neurons / Q000637:transplantation*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000637:transplantation; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1
keywords: Axonal guidance; GDNF; Lentivirus; Netrin-1; Parkinson's disease; Tyrosine hydroxylase; Ventral mesencephalon (VM) transplantation